1) Field of the Invention
The present invention relates to a safe therapeutic agent for oral and intramuscular application which can be administered to patients diagnosed as being afflicted with renal diseases, among others nephrotic syndrome, and patients with hepatic disorders such as viral or drug-induced heptitis, thereby permitting such patients to attend hospitals as an outpatient. Special attention should be directed to the facts that such renal diseases in recent years tend to occur with greater frequency not only in the senile but also young generations and that the nephrotic syndrome is considered to be a step of inducing chronic renal insufficiency.
2) Background of the Invention
As an internal therapeutic drug for lipoid nephrosis or minimal change nephrotic syndrome, there have been employed chemically synthesized steroids or dipyridamole, a antiplatelet drug, which however require prolonged administration and, upon application to the younger generation, are accompanied with great apprehension for the onset of side effects, such as full-moon face, menstrual disorders, dizziness, headache, nausea and vomiting, as well as, in the serious cases, infections, gastrointestinal bleeding, metabolic disorders, osteoporosis, thrombosis, adrenal insufficiency and mental disorders.
Hepatitis, which disease is roughly classified into the viral and drug-induced types, occurs mostly in the form of viral type, and the biological response modifiers (hereinafter referred to briefly as "BRMs"), for example interferons and interleukin 2, and Minofagen C, an intravenous injectable preparation of glycyrrhizin, are put in clinical use as a treatment agent against hepatitis. Nevertheless, BRMs are found to cause side effects such as fever, and encounter difficulties in consecutive administration over an extended period of time, while glycyrrhizin, belonging essentially to an anti-inflammatory agent, requires the management of hypertension and electrolytes for the prolonged administration. In addition to these, Saikosaponin, saponin, Gomishin, etc. are known but have never put into clinical application so far.
As water-soluble polysaccharides having poly-D-galacturonic acid of the following formula (I): ##STR1## (wherein the carboxyl group(s) may be esterified with methyl), there are known, for example, pectic substances which are water-soluble polysaccharides composed mainly of poly-D-galacturonic acid being obtained by extracting the fruit rinds of oranges with an acidic aqueous solution, effecting demethylation with an acid, alkali or enzyme, and then precipitating by adding organic solvent such as alcohols. The water-soluble pectic substances are grouped into pectin and pectinic acid according to the degree of methyl esterification of the carboxyl groups in the poly-D-galacturonic acid, whereas the counterpart being substantially free from any methyl ester remained is called pectic acid.
Water-soluble pectic substances are mainly used in the food industry as a starting material for jellies, etc. but have hardly found application as a pharmaceutical except that they are employed to cover the mucous membranes.
The present invention, in one aspect, utilizes the extracted component of Tanjin. Tanjin is a medical plant that has been traditionally used in China for its efficacies of improving blood circulation and ameliorating the blockade of blood circulation. With regard to Tanjin, in recent years, many reports have been published in Japan and abroad on their various pharmacological activities, for example, vasodilating activity (Hikoyoshi Ohura: Wakan Iyaku Gakkai-shi (Journal of the Society of Japanese-Chinese Drugs Association), 5: 227-237, 1988), hypotensive activity (Nakayama Igakuin-ron, published by Ishiyaku Shuppan Co., Tokyo, 257-258, 1980), inhibitory activity against blood coagulation (Koui Ra: Acta Pharmaceutica Sinica, 23 (11); 830-834, 1988), inhibitory activity against intracellular cholesterol synthesis (Sun Xi-ming; Chu-Yaku-Soh (Chinese Medical Plants), 22 (1): 20-23, 1991), hepatocyte protecting activity (I Shinko et al: Chuh-Sei-I Ketsugo Zasshi (Chinese-Western Medicine Conjugating Gazette): 11 (2), 102-104, 1991) and radical scavenging activity (Ko Tenki: Journal of Shanghai Chinese Drugs Association, 9: 28-30, 1988), as well as on the improvement of renal function (Hikoyoshi Ohura: Proceedings of the 2nd Chinese-Japanese Symposium on Medical and Pharmaceutical Research on Japanese-Chinese Drugs: pp.148-157, 1988) and efficacy in patients with chronic renal diseases and uremia (Cho Kyohjin: Journal of Shanghai Chinese Drug Association, 1, 17-18, 1981). However, these reports mentioned nothing on the identification of active substances showing such activities or efficacies, except the low-molecular-weight substances which differ entirely from what the present invention refers to.
At the same time, extensive research activities have been under way on the therapeutic drugs for renal diseases based on Tanjin, resulting for example in isolation of tansinone homologs that belong to low-molecular-weight phenanthrenequinones and magnesium lithosperminate B, a tetramer of caffeinic acid (T. Yoozawa, H. Y. Chung, H. Oura, G. Nagaoka and I. Nishioka; Chem. Pharm. Bull., 36, 316 (1988)), all of which are highly lipo-soluble substances obtained by extraction with solutions containing organic solvents and have not yet found clinical application.
Renal or kidney diseases can be roughly classified into the primary type involving the glomeruli and the secondary type originating from other diseases, with the former accounting for more than 80% of total onset and occurring more frequently in the younger generation, being occupied by about 90% of the occurrence. From the standpoint of histopathological findings, the diseases are grouped into minimal change nephrotic syndrome, glomerulosclerosis, membranous nephritis, mesangial proliferative glomerulonephritis (IgA nephritis and non-IgA nephritis), membranous proliferative glomerulonephritis, crescent-forming glomerulonephritis, etc. Proteinuria is observed as a clinical finding commonly among all histopathological types of diseases, whereby the serious proteinuria leads to the diagnosis as a nephrotic syndrome. Since the kidney diseases, especially those induced by the organic degeneration of the kidney, are taking place increasingly not only in the old or senile but also younger generations, furthermore, there is a strong demand for the development of a water-soluble drug based on a plant component having reduced side effects which is able to be administered to patients orally or intramuscularly to treat the disorders through organic amelioration.
On the other hand, hepatitis, which is roughly categorized into the viral type and the type induced by drugs such as alcohol, is caused overwhelmingly by infection with hepatitis B and C viruses. Nowadays, it has been reported that interferon is particularly effective in treating the hepatitis C, with its application becoming more frequent (S. Iino et al.: "Kiso to Rinsho" (Fundamental and Clinical), 26, 339, 1992; H. Suzuki et al.: "Kan.Tan.Sui" (Liver. Gallbladder.Pancreas); 23, 1065, 1991). However, interferon, when applied for a short period of time, is found to cause influenza-like symptoms such as fever, while in the case of prolonged administration, it is noted to bring about adverse effects such as loss of weight, diarrhea, vomiting, arrhythmia, depilation and abnormalities in autoimmunity. In the light of the fact that the conventional drugs are in the form of injectable solution, there is a strong demand for the development of a simple and practically employable, novel therapeutic agent or a water-soluble medicine based on a plant drug or a component of a medical plant causing reduced side effects, which medicine is able to be administered patients orally or intramuscularly as a supplementary drug in combination with interferon, etc. for the treatment of hepatitis.
The present inventors conducted intensive investigation into such a drug substance on the basis of the widely employed nephrotic syndrome model realized in rats by puromycin which is well known to generate markedly proteinuria and to exhibit organic changes in the kidney, and as a result, found that the aqueous extract of Tanjin contains the polysaccharides which is effective for the above-described model and that the polysaccharides are composed mainly of poly-D-galacturonic acid.